Juvenile osteopetrosis is an inherited skeletal disorder resulting from reduced osteoclast-mediated bone resorption. Activation of osteoclasts is known to promote bone resorption and alleviate the disease and associated symptoms. Vitamin D-binding protein-macrophage activating factor (DBP-MAF) is a newly discovered osteoclast activator, which has shown therapeutic potential in animal models. An impaired osteoclast activity (leading to osteopetrosis) has been recently shown to be due to a generalized defect in enzymatic conversion of DBP (vitamin D binding protein) to DBP-MAF by T- and B- lymphocytes in both humans and animal models. Infusions of ex vivo generated DBP-MAF has been shown to increase osteoclast mediated bone resorption in animal models. This warrants further research to evaluate the therapeutic potential of DBP-MAF human osteopetrosis. A clear understanding of the underlying mechanism of osteoclast activation by DBP-MAF in humans is necessary to develop DBP-MAF as a therapeutic agent for osteopetrosis. We propose to achieve this goal by (i) Systematic evaluation of DBP- MAF mediated activation of osteoclasts from normal and osteopetrotic subjects and (ii) Determining the functionality of DBP, osteoclasts and DBP-MAF from osteopetrotic children. The proposed research not only intends to gain an insight towards the cellular and/or molecular defects leading to an excessive accumulation of bone in osteopetrotic subjects, but also offers a unique opportunity of methodology development to determine the underlying defect in a given 'clinical case', which would lead to a better course of therapeutic options.